Abstract Context Hyperhomocysteinemia is common in patients with kidney disease and is potentially linked to increased cardiovascular risk. While folate-based supplementation effectively lowers homocysteine levels, its clinical benefits in kidney disease remain uncertain. Objective This systematic review and meta-analysis aimed to evaluate the effects of folate-based supplementation on homocysteine levels, kidney function, cardiovascular events, mortality, and safety in adult patients with acute kidney injury (AKI) or chronic kidney disease (CKD). Data sources Following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, we searched PubMed, Embase, Web of Science, MEDLINE, CINAHL, and CENTRAL from database inception to March 24, 2024. Data extraction Randomized controlled trials (RCTs) and nonrandomized trials comparing folate-based supplementation with placebo, no intervention, or alternative folate formulations in adults with AKI or CKD were included. Two reviewers independently screened studies, performed full-text review, and extracted data. Data analysis A total of 37 studies with 8625 participants (35 RCTs, 2 non-RCTs) were included. All studies enrolled patients with CKD, and no eligible AKI studies were identified. Random-effects meta-analyses were conducted using mean differences (MDs) and risk ratios (RRs) with 95% CIs. Folate-based supplementation significantly lowered plasma homocysteine (14 RCTs; MD, −8.09 µmol/L; 95% CI, −11.54 to −4.63; I2 = 98%), with adverse events comparable to controls. However, no statistically significant reductions were observed in cardiovascular events (6 RCTs; RR, 0.88; 95% CI, 0.68-1.13; I2 = 13%), all-cause mortality (8 RCTs; RR, 1.02; 95% CI, 0.92-1.13; I2 = 0%), or cardiovascular mortality (7 RCTs; RR, 0.99; 95% CI, 0.75-1.29; I2 = 0%). Evidence for kidney function was limited; 2 RCTs reporting serum creatinine showed no significant effect (MD, −0.27 mg/dL; 95% CI, −1.29 to 0.74; I2 = 0%), whereas findings for long-term kidney disease progression were inconsistent. Subgroup and sensitivity analyses suggested more favorable point estimates among patients with end-stage kidney disease, higher folate dosages, alternative folate forms, shorter treatment durations, and lower baseline folate levels, but none reached statistical significance. Conclusions Folate-based supplementation effectively lowers homocysteine in CKD but does not significantly reduce cardiovascular events or mortality, and there is insufficient evidence to support an effect on renal outcomes. Although a nonsignificant 12% relative reduction in cardiovascular events was observed, a trial of approximately 3174 participants would be required to adequately power detection of such an effect. Routine folate supplementation in CKD without another indication is therefore not supported by current evidence. The complete absence of eligible AKI studies highlights a critical research gap, and future adequately powered trials are warranted to clarify the role of folate in both CKD progression and AKI recovery. Systematic Review Registration PROSPERO registration No. CRD42024589377.
Chan et al. (Thu,) studied this question.